Normal wound healing involves three sequential phases: inflammation, proliferation/scar formation, and remodeling.
In chronic wounds, such as those that occur following severe tissue damage, or those that occur in patients with diabetes or chronic venous insufficiency, macrophages are stalled at the inflammation phase of healing (Acosta et al. Intl Wound J., 5: 530-539(2008), exhibiting an “M1” phenotype). The pro-inflammatory cytokines, reactive oxygen species, and danger signals released by these macrophages cause extensive damage to the tissue, resulting in wounds that fail to heal. However, the lingering presence of “M2A” macrophages, those that control the proliferative phase of healing, result in dense fibrous scarring. The macrophage population must further transition to the “M2C phenotype,” to promote remodeling.
Hydrogels that inhibit the behavior of M1 macrophages via release of anti-inflammatory molecules are numerous (Repithel® from Munipharma, Germany, described in Beukelman et al. Burns, 34: 845-855 (2008)). However, anti-inflammatory technologies are known to inhibit wound healing (for example, Stadelmann 1998 American Journal of Surgery 176: 39S-47S) because inflammation is required for healing. Encapsulation of mesenchymal stem cells causes macrophage polarization to a M2-like phenotype (Hanson et al., Tissue Engineering Part A, 17: 2463-2471 (2011)).
However, none of these technologies promotes the natural wound healing sequence observed in healthy wound healing. Even technologies that could promote the release of macrophage-stimulating cytokines do not ensure that the proper cytokines are released after M2A macrophage behavior subsides, which is crucial to the wound healing process.
Therefore, a need exists in the art for improved methods for wound healing by promoting proper macrophage behavior.